Compounds of the cyclopentano-polyhydrophenanthrene series and a process for the manufacture of the same



Patented July 18, 1944 I COMPOUNDS 6F THE CYOLOPENTANO-POLYHYDROPHENANTHRENE SERIES AND A PROCESS FOR THE MANUFACTURED! THESAME Adolf Butenandt, Berlin-Dalilem,

and Jose! Schmidt-Theme, Berlin-Zelilendori', Germany, and ErwinSchwenk, Bloomfield, N. 1., assignon to Scherlng Corporation.Bloomfield, N. J., a corporation 01 New Jersey No Drawing. ApplicationJune 30, 1939, Serial No. 282,126. In Germany July 1, 1938 19 Claims.(Cl. zoo-397.4)

This invention relates to compounds of the described a process for themanufacture of compounds of the cyclopentanopolyhydrophenan 'threneseries, wherein, compounds of this series which exhibit on thecarbon-1'7 a side chain, in

which in adjacent position to a keto group a reactive methyl ormethylene group is located, are condensed with oxo compounds and thecondensation products subjected to an oxidation process.

In accordance with the present invention keto compounds of theandrostane and estrane series are condensed with oxo compounds such asketones in the presence of alkaline reacting substances, such as thealkali and alkaline earth metals, for example sodium, potassium,magnesium, metal alcoholates, such as sodium alcoholate and so on, asare described for example in Houben-Weyl, Die Methoden der organ.Chemie, 1922, vol. 2, page 693 et seq. The condensation also takes placehere with the methylene group in adjacent position to the keto group,whereby compounds are obtained which instead of the methylene groupcontain a C=C bond.

Particularly valuable compounds are obtained whencyclopentano-polyhydrophenanthrene compounds are employed as startingmaterials in the case of which a keto group is present in 17-position,The condensation then takes place on the C-atom 16.

As ketones there can be employed both symmetrical ketones, as forexample acetone, and also mixed ketones, as for example methyl-ethylketone, methyl-propyl ketone and the like, and also i aromatic ketones,as for example benzophenone or acetophenone and the like. However, alsoother oxo compounds as for example aldchydes can be employed.

The condensation products obtained are then '1 subjected to an oxidationprocess, for example with ozone, whereby the double bond produced in thecondensation is ruptured with formation of a keto group, so thata,p-diketones are obtained. Instead of ozone also other energeticoxidising agents can be employed, which are capable of splitting up acarbon-carbon double bond, as for example chromic acid, lead andmanganese tetraacetate, alkali permanganates, and per-iodic acid; ifdesired the oxidation can also be carried out in such a manner that atthe double bond there are first added on in the manner known per so twohydroxyl groups, for example by means of osmium tetroxlde and then thefurther oxidation is carried out with one or the above mentioned agents.In this manner the same cap-d1- ketones are obtained.

These can it desired be converted by reduction, for example withzinc-glacial acetic acid, into keto alcohols and further byhydrogenation, for example with Raney nickel, into the correspondingmflrs y ls.

For the oxidation it is in some cases suitable to protect hydroxyl orother sensitive groupings present in the ring system by esterification,etherification or other conversion into such groups as can be againreconverted into hydroxyl and the like groups. Similarly, where thestarting compound has one or more double bonds, these may be protectedagainst the action of the oxidizing agent in known manner byintermediate saturation with a substituent oi the type which cansubsequently be split off to restore the double bond or bonds.

The following examples illustrate the invention:

EXMIPLI 1 Condensation of dehudroandrosterone acetate with methyl-ethylketone 10 grams of dehydroandrosterone acetate are dissolved in 45 ccs.of methyl-ethyl ketone and 30 cos. of ether and the mixture allowed toflow into 9 grams of sodium in 30 cos. 0! ether. The whole is heated toboiling for half an hour. Thereupon 25 ccs. of glacial acetic acid areallowed to flow in and subsequently so much water that all passes intosolution. The ether layer is separated and washed with water, sodiumhydroxide solution and water. To the residue remaining after theevaporation of the ether, there are added 15 grams of Guard-Reagent T(trimethylaminoacetohydrazide hydrochloride-Helm Chim. Acta, 19, 1095(1936)) and ccs. of alcohol, 2 cos. of water and 2 ccs. of glacialacetic acid. The mixture is boiled for half an hour. By this meansproducts which have been produced by condensation of the methyl-ethylketone with itself are removed while the condensation product of thedehydroandrosterone does not react with Girard- Reagent. The reactionsolution is poured into 1 litres of water, extracted with ether andwashed with water, sodium hydroxide solution and water. The residueremaining after drying gives on crystallisation from acetone 3.8 gramsof condensation product of M. P. 161-68 C. The mother liquors aredistilled in high vacuum at C. The liquid products which pass over firstare separated. On iurther high vacuum distillation there passes over at180 C. 1 gram condensation product. Total yield 4.8 grams. M. P. 01' thepure product 174-76 C.

The condensation with dehydroandrosterone treated with 30 cos. ofalcohol. 8 grams of Girard- Reagent T and 3 ccs. of glacial acetic acidand the mixture boiled for hall an hour. Thereupon the whole is pouredinto 300 ccs. of ice cold under the same conditions yields the sameprod- 5 water, which contains so much sodium carbonate not. By theapplication of magnesium as conthat bromo-thymol is not quite changed toblue. densing agent, and with the dehydroandrosterone and extracted withether. The water layer is in benzene solution, the same result isobtained. separated and acidified with so much sulphuric acid that thesolution is 1 N as regards acid. Enron 2 After 2 hours the precipitatedroduct is filtered off (or extracted with ether), washed with so-Condensation of dehydroandrosterone acetate dlum hydroxid solution andwater and mm acetone After the crystallisation from methanol there areobtained 330 mg. of a substance 01 M. P. 187-90 By corres ondingcondensation of deh m' C. The analytically pure product melts at 190-androsterone acetate with acetone 9. condensa- It crystamses with 1 mo]of water of tion product of M. P. 222-23 C. is obtained whichcrystallisation. r product is t 3 t 5 crystallises fmm almmbwater inneedlesandrostenol-(16) -one-(17) (IV) or the 3-acet- 3oxy-M-androstenol-(ll) -one-(l6) (V). In the u 20 debromination withzinc dust simultaneously one of the keto groups of the 16.17-diketone(III) iiffifisititi primal-11y mission 18 to the alcohol group. (In theaqueous alkali so- 4 grams of condensation product are boned in lutionwhich is employed for extracting the ether 10 cos.' of acetic anhydridefor 10 minutes. To solution of the ozonisation pmductthere is pres thehot solution water is added to the point of em an ocetoxy'dicarboxyncacid produced by turbidity. On cooling the acetate crystallises out.Splitting of the 54mg) By reaction of the acetoxy-androstenolone (IVAfter filtering of! and washing with water there or V) withhydroxylamine acetate in alcohol are obtained from acetone 3.9 grams oiacetate II in needles of M P c the monoxime is obtained whichcrystallises from alcohol in leaflets of M. P. 244 C. (with decom- Wu 4position).

I By the action of acetic anhydride-pyridine Conversion of thecondensation products into in the cold the dlaceta-te 0! the16.17-(11018. Ozonisatton of the 3-ocetate of the andmstenolone 15Obtained which forms needles condensation product of dehydroandrosteroneof with methyl ethyl ketone M 5 3 grams of the acetate of thecondensation R duct, 0 m 340cm s ostenolo product (II) are ozonised inportions of 200 mg. 40 e n f e each according to the following method:200 0 of the acetate 1v or v are hydromg. 01 acetate are dissolved in 5cos. of chlorogenated up t t u in ethyl t t with form, 2 ccs. of brominesolution (corresponding, Raney nickel. After filtering oi! the nickeland to 1 mol bromine) introduced and f r 3 minutes evaporation of theethyl acetate there is obtained ozone passed thr the solution o dfromacetone the 3-acetoxy-M-androstendioling to about 100 ccs. of 6% ozone).The ch oro- (16.17) (VI) in leaflets of M. P. 179 C. It is alform isblown oil in the cold by an air stream and lowed to stand over night atroom tempe ature the residue boiled in 5 ccs. of glacial acetic acidwith pyridine-acetic anhydride and in this with the addition-oi 500 mg.of zinc dust for ner converted t the Auandmstentriol. 10 minutes. Thezinc is filtered oil and the so- 6 (3.16.17)-triacetate (VH), whichcrystallises in lution poured into water. The portions now prismaticneedles of M. P. 222-24" C. combined are together extracted with etherand The reaction may be illustrated by the 1 1- the ethereal solutionwashed with sodium hylowing formulae which show the conversion ofdroxide solution and water. The residue reandrostenolone intoandrostenol-dione and anmaining after the evaporation of the ether isdrosten-triol:

on. on, 0 on. on. on; on, 0

l l on, on. l l CIHI CsHl L/ cmooolm .AcO Na H0 Aoylation AcO Bn CH: CH:0 I OH] CHI 0 CH: CH: 0

c o 7 on Zn I AcO 0| .AcO Aoeticaoid AeO l I m I may Of course, manychanges and variations may be made in the reaction conditions by thoseskilled in the art in accordance with the princi- Dies set forth hereinand in the claims annexed hereto.

What we claim is:

1. Process for the manufacture of compounds of thecyclopentano-polyhydrophenanthrene series, wherein a member of the groupconsisting of saturated and unsaturated ketones of the androstane andestrane series is condensed with an oxo compound in the presence of anagent capable of condensing a carbonyl group with a nuclear methylenegroup.

2. Process as claimed in claim 1 in which the condensation takes placein the presence of an alkaline reacting substance.

3. Process as claimed in claim 1 in which as condensing agent analkalimetal is employed.

4. Process as claimed in claim 1 in which the condensation product issubjected to an oxidation process to rupture the double bond produced inthe condensation and to form a,,8-diketones.

5. Process as claimed in claim 1, in which as starting materials aketone of the androstane series is employed.

6. Process as claimed in claim 1, in which as starting material there isemployed a member of the group consisting of dehydroandrosterone and itsderivatives wherein the 3-hydroxyl group is replaced by a groupconvertible with the aid of hydrolysis into hydroxyl.

7. Process as claimed in claim 1, in which double bonds present in thering system are protected by adding on such substances as can again besplit ofl. with reformation of the double bond.

8. Process as claimed in claim 1, in which in the application ofstarting materials containing hydroxyl groups these latter are protectedby conversion into groups which can again be reconverted into thehydroxyl group by hydrolysis.

9. Process for the manufacture of a,fl-diketones of the androstane andestrane series wherein the condensation products of the ketones of thesaid series with oxo-compounds are subjected to an oxidation processwith ozone.

10. Process for the manufacture of compounds of the androstane andestrane series having an alcohol group in at least one of the 16 and 17positions, comprising subjecting a 16,17-diketone obtained by oxidationof the condensation product of a ketone of the androstane and estraneseries with an oxo compound, to the action of an agent capable ofreducing a keto group to an alcohol group.

11. Process as claimed in claim 10 wherein as reducing agentzinc-glacial acetic acid is employed for the manufacture of ketoalcohols.

12. Process as claimed in claim 10 wherein as reducing agent Raneynickel is employed for the manufacture of glycols.

13. 3-acetoiw-As-androstenol-16-one-1'7.

14. 3 acyloxy As androstenolone, the keto group being in one of the 16and 17 positions and the hydroxy group being in the other of suchpositions.

l5. 3 acetoxy As androstenolone, the keto group being in one of the 16and 17 positions and the hydroxy group being in the other of suchpositions.

16. Process for the manufacture of compounds of the androstane andoestrane series having. an alcohol group in at least one of the 16 and17 positions, comprising subjecting a 16,17-diketone of the androstaneand oestrane series to the action of an agent capable of reducing a ketogroup to an alcohol group.

17. Process for the manufacture of a,fl-d1ke- VII tones of theandrostane and oestrane series wherein the condensation products of theketones of the said series with oxo-compounds are subjected to anoxidation process with an agent capable of splitting of! the radical ofthe oxocompound and replacing it with ketonic oxygen.

18. Process for the manufacture of glycols of the cyclo pentanopolyhydro-phenanthrene series, comprising condensing a member of thegroup consisting of saturated and unsaturated ketones of the androstaneand oestrane series with an oxo compound, in the presence of an agentcapable of promoting condensation of a carbonyl group with a nuclearmethylene group, subjecting the condensation product to an oxidationprocess to rupture the double bond produced by the condensation and forman a,p-diketone, and thereafter reducing the diketone to thecorresponding glycol.

19. Process according to claim 18, wherein the reduction is effectedfirst by treatment with nascent hydrogen, and thereafter withcatalytically activated hydrogen.

' ADOLF BUTENAND'I'.

JOSEF scmnn'r-momn. ERWIN SCHWENK.

